Pharmaceutical dosage form for pulsatile delivery of d-threo-methylphenidate and a second CNS stimulant

ABSTRACT

Novel pharmaceutical dosage forms provide for pulsatile delivery of d-threo-methylphenidate and a second CNS stimulant, i.e., release encapsulated drug in spaced apart &#34;pulses.&#34; The second CNS stimulant may be an analeptic agent or a psychostimulant, with analeptic agents preferred. The dosage forms may comprise capsules housing compressed tablets or drug-containing beads or particles, or may comprise a tablet with the first, second and optionally third dosage units each representing an integral and discrete segment thereof. Methods of treatment using the pharmaceutical dosage forms are provided as well.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSerial No. 60/127,984, filed Apr. 6, 1999.

TECHNICAL FIELD

The present invention relates generally to drug delivery, and morespecifically relates to novel pharmaceutical dosage forms that providepulsatile delivery of d-threo-methylphenidate in combination with asecond CNS stimulant. The invention additionally relates to methods foradministering methylphenidate using the novel dosage forms.

BACKGROUND

Pharmaceutical dosage forms are known which provide a variety of drugrelease profiles, including immediate release, sustained release, anddelayed release. That is, it may be desirable, for a particular drug, toprevent drug release after drug administration until a certain amount oftime has passed (so-called “timed release”), to provide substantiallycontinuous release over a predetermined time period (so-called“sustained release”) or to provide release immediately following drugadministration (i.e., “immediate release”). For some types of drugs, itis preferred to release the drug in “pulses,” wherein a single dosageform provides for an initial dose of drug followed by a release-freeinterval, after which a second dose of drug is released, followed by oneor more additional release-free intervals and drug release “pulses.”Pulsatile drug delivery is useful, for example, with active agents thathave short half-lives and must be administered two or three times daily,with active agents that are extensively metabolized presystemically, andwith active agents which lose the desired therapeutic effect whenconstant blood levels are maintained. These types of agents havepharmacokinetic-pharmacodynamic relationships that are best described bya clockwise “hysteresis loop.” A drug dosage form that provides apulsatile drug release profile is also useful for minimizing the abusepotential of certain types of drugs, i.e., drugs for which tolerance,addiction and deliberate overdose can be problematic.

Because a precise and effective pulsatile drug delivery system isdifficult to formulate and manufacture, there are few such dosage formsthat have been commercialized. There are, however, several patents andliterature references pertaining to pulsatile drug delivery. See, forexample, U.S. Pat. No. 5,413,777 to Sheth et al., directed to apulsatile once-a-day delivery system for the administration ofminocycline; U.S. Pat. No. 5,260,068 to Chen, directed to amultiparticulate pulsatile drug delivery system; U.S. Pat. No. 4,777,049to Magruder et al., directed to an osmotic delivery system for constantrelease of a drug with intermittent release “pulses”; U.S. Pat. No.5,391,381 to Wong et al., directed to a drug dispenser for deliveringindividual drug-containing units in a “pulsatile” manner; PCTPublication No. WO 98/32424, pertaining to pulsatile delivery ofdiltiazem hydrochloride; U.S. Pat. Nos. 5,472,708 and 5,260,069 to Chen;Ishino et al. (1992) “Design and Preparation of Pulsatile Release Tabletas a New Oral Drug Delivery System,” Chem. Pharm. Bull.40(11):3036-3041; Cohen et al. (1994), “Pulsatile Release fromMicroencapsulated Liposomes,” J. Liposome Res. 349-360; and Gazzaniga etal. (1994), “Chronotopic Drug Delivery Systems for Pulsatile and/orSite-Specific Release,” 21^(st) . Proc. Int. Symp. Controlled ReleaseBioact. Mater., pp. 744-745.

The present invention is directed in part to a novel pulsatile drugdelivery system which is straightforward to manufacture and providesprecisely timed drug release “pulses” at desired intervals.

Methylphenidate hydrochloride (HCl), the hydrochloride salt ofα-phenyl-2-piperidine-acetic acid methyl ester (available commerciallyas Ritalin®), is a central nervous system stimulant that is used in thetreatment of Attention Deficit Disorder (“ADD”), a commonly diagnosednervous system illness in children that is characterized by bothdistractability and impulsivity. Methylphenidate HCl is also used totreat a related disorder, Attention Deficit Hyperactivity Disorder(“ADHD”), in which symptoms of hyperactivity are present along with thesymptoms of ADD. The drug is additionally used in the symptomatictreatment of narcolepsy, depression, and the cognitive declineassociated with Acquired Immunodeficiency Syndrome (“AIDS”) orAIDS-related conditions, as well as for mood elevation, particularly interminally ill patients with diseases such as cancer. Methylphenidateexists as four distinct isomers, as follows:

The drug as used in therapy is a racemic mixture of the d- and l-threoenantiomers, which have been acknowledged as more active than theerythro pair.

Because of its potential for tolerance (loss of clinical efficacy whenconstant blood levels are maintained), short-half life and potential forabuse, methylphenidate is a primary candidate for use in conjunctionwith the drug delivery systems of the invention.

It has recently been found that the d-threo enantiomer ofmethylphenidate, rather than the l-threo enantiomer, is primarilyresponsible for the therapeutic effectiveness of methylphenidate,particularly in ADHD. See Srinivas et al. (1992), “EnantioselectivePharmacokinetics and Pharmacodynamics of d,l-threo-Methylphenidate inChildren with Attention Deficit Hyperactivity Disorder,” Clin.Pharmacol. Ther. 52:561-568, who compared the results of administeringdl-threo, d-threo, and l-threo methylphenidate to children sufferingfrom ADHD, and determined that the pharmacodynamic activity ofmethylphenidate resides in the d-threo isomer. Ding et al. (1997),“Chiral Drugs: Comparison of the Pharmacokinetics of [¹¹C]d-threo andl-threo-Methylphenidate in the Human and Baboon Brain,”Psychopharmacology 131:71-78, and Eckerman et al. (1991),“Enantioselective Behavioral Effects of threo Methylphenidate in Rats,”Pharmacology Biochemistry & Behavior 40:875-880, also studied therelative therapeutic efficacy of the d-threo and l-threo isomers,concluding that d-threo-methylphenidate was responsible for thetherapeutic efficacy of the racemate.

It has also been suggested that l-threo methylphenidate not only makesno contribution to therapeutic efficacy, but in fact contributes toundesirable side effects associated with administration of racemicmethylphenidate, e.g., insomnia, euphoria, development of tolerance tothe drug, and potential for abuse. Accordingly, several researchers haveproposed administering methylphenidate as the pure d-threo isomer ratherthan as the racemic mixture of d-threo and l-threo isomers. See, e.g.,U.S. Pat. No. 5,908,850 to Zeitlin et al., U.S. Pat. No. 5,874,090 toBaker et al., and U.S. Pat. No. 5,922,736 to Dariani et al. Also seeU.S. Pat. No. 5,837,284 to Mehta et al., which describes a pulsatiledrug delivery system for administration of d-threo methylphenidate.

A drawback of the prior art, however, is that the disclosed dosage formsare ineffective for individuals who do not respond, or respondinadequately, to methylphenidate therapy or to a second central nervoussystem (“CNS”) stimulant (e.g., an analeptic agent such asd-amphetamine, as found in the commercial ADHD product Adderol®). It hasnow been discovered that co-administering methylphenidate, andparticularly d-threo methylphenidate, with a second CNS stimulant,particularly an analeptic agent such as d-amphetamine, gives rise to atherapeutically effective pharmaceutical formulation useful in treatingindividuals who do not respond, or respond inadequately, tomethylphenidate therapy or to the second CNS stimulant, whenadministered as individual active agents. It has also been found thatthe aforementioned combination of active agents can provide an increasedtherapeutic benefit to patients who do respond to methylphenidatetherapy or to the second CNS stimulant, e.g., to an analeptic agent suchas d-amphetamine.

Accordingly, the present invention provides novel pharmaceutical dosageforms for the administration of d-threo methylphenidate along with atleast one additional active agent comprising a second CNS stimulant. Thenovel dosage forms provide for pulsatile drug release, therebymaximizing efficacy (i.e., the loss of clinical efficacy over time),reducing the potential for abuse or noncompliance. The dosage forms alsoprovide for therapeutic efficacy in individuals who do not respond, orrespond inadequately, to methylphenidate or to the second CNS stimulantwhen these agents are administered alone, and provide enhancedtherapeutic efficacy in individuals who are responsive tomethylphenidate and other CNS stimulants such as d-amphetamine. No artof which applicants are aware describes drug delivery systems as nowprovided herein.

To the best of applicants' knowledge, the pharmaceutical dosage forms ofthe invention are previously unknown and completely unsuggested by theart.

SUMMARY OF THE INVENTION

Accordingly, it is a primary object of the invention to address theabove-mentioned need in the art by providing a pharmaceutical dosageform for pulsatile delivery of d-threo methylphenidate, wherein thedosage form contains a second CNS stimulant as an additional activeagent.

It is another object of the invention to provide such a dosage formcomprising at least two individual drug-containing dosage units, each ofwhich has a different drug release profile.

It is another object of the invention to provide such a dosage formwherein the dosage units are housed in a closed capsule.

It is still another object of the invention to provide such a dosageform wherein the dosage units are compressed tablets.

It is yet another object of the invention to provide such a dosage formwherein the dosage units are drug-containing particles or beads.

It is a further object of the invention to provide such a dosage formcomprised of a single tablet of which the drug-containing dosage unitsrepresent integral and discrete segments.

It is still a further object of the invention to provide such a dosageform wherein the second CNS stimulant is an analeptic agent orpsychostimulant.

It is an additional object of the invention to provide methods foradministering methylphenidate using the novel dosage forms.

Additional objects, advantages and novel features of the invention willbe set forth in part in the description which follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Nomenclature:

Before the present formulations and methods of use are disclosed anddescribed, it is to be understood that unless otherwise indicated thisinvention is not limited to specific pharmacologically active agents,specific pharmaceutical carriers, or to particular administrationregimens, as such may vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an active agent” includes mixtures of active agents, “asecond agent” includes more than one “second” agent, reference to “apharmaceutical carrier” includes combinations of two or more carriers,and the like.

In this specification and in the claims which follow, reference will bemade to a number of terms which shall be defined to have the followingmeanings:

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

The terms “active agent,” “drug” and “pharmacologically active agent”are used interchangeably herein to refer to a chemical material orcompound which, when administered to an organism (human or animal,generally human) induces a desired pharmacologic effect. In the contextof the present invention, the terms refer to a compound that is capableof being delivered orally.

By the terms “effective amount” or “pharmaceutically effective amount”of an agent as provided herein are meant a nontoxic but sufficientamount of the agent to provide the desired therapeutic effect. The exactamount required will vary from subject to subject, depending on age,general condition of the subject, the severity of the condition beingtreated, and the particular active agent administered, and the like.Thus, it is not possible to specify an exact “effective amount.”However, an appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation.

By “pharmaceutically acceptable” carrier is meant a carrier comprised ofa material that is not biologically or otherwise undesirable, i.e., thematerial may be administered to an individual along with the selectedactive agent without causing any undesirable biological effects orinteracting in a deleterious manner with any of the other components ofthe pharmaceutical composition in which it is contained. The term“carrier” is used generically herein to refer to any components presentin the pharmaceutical formulations other than the active agent oragents, and thus includes diluents, binders, lubricants, disintegrants,fillers, coloring agents, wetting or emulsifying agents, pH bufferingagents, preservatives, and the like.

Similarly, a “pharmaceutically acceptable” salt or a “pharmaceuticallyacceptable” ester of a compound as provided herein is a salt or esterwhich is not biologically or otherwise undesirable.

In the chemical structures drawn herein, the use of bold and dashedlines to denote particular conformation of substituents follows IUPACconvention. The symbols “α” and “β” indicate the specific stereochemicalconfiguration of a substituent at an asymmetric carbon atom in achemical structure as drawn. Thus “α,” denoted by a broken line,indicates that the group in question is below the general plane of themolecule as drawn, and “β,” denoted by a bold line, indicates that thegroup at the position in question is above the general plane of themolecule as drawn.

“Pulsatile Release” Dosage Forms:

In a first embodiment, the invention features pharmaceutical dosageforms that provide for pulsatile delivery of d-threo-methylphenidate,with a second CNS stimulant co-administered with thed-threo-methylphenidate in at least one of the drug release “pulses.” By“pulsatile” is meant that a plurality of drug doses are released atspaced apart time intervals. Generally, upon ingestion of the dosageform, release of the initial dose is substantially immediate, i.e., thefirst drug release “pulse” occurs within 1-2 hours of ingestion. Thisinitial pulse is followed by a first time interval during whichsubstantially no drug is released from the dosage form, after which asecond dose is then released. Typically, the second dose is released onthe order of 3-5 hours following ingestion of the dosage form.Preferably, release of the second dose is followed by a secondnon-release interval, which is again followed by a “pulse” of drugrelease. Ideally, release of a third dose occurs on the order of 7-9hours following ingestion. In a preferred embodiment herein, either twoor three release pulses are provided. However, the invention is alsointended to encompass dosage forms that provide more than three pulses,with non-release intervals therebetween of approximately 2-6 hours,preferably 3-5 hours.

The aforementioned pulsatile release profile is achieved with dosageforms that, in one embodiment, are closed and preferably sealed capsuleshousing two or more drug-containing “dosage units.” In a preferredembodiment, each dosage unit comprises a compressed or molded tablet,wherein each of the tablets within the capsule provides a different drugrelease profile. That is, for an exemplary dosage form, a first tabletreleases drug substantially immediately following ingestion of thedosage form, while a second tablet in the capsule releases drugapproximately 3-5 hours following ingestion, and an optional thirdtablet provides drug release after approximately 7-9 hours. While thedosage form will not generally include more than three tablets, dosageforms housing four or more tablets are within the scope of the presentinvention.

In an alternative embodiment, each dosage unit comprises adrug-containing particle or bead (drug-containing “beads” refer todrug-coated inert supports, e.g., lactose beads coated with drug). Afirst group of these particles or beads releases drug substantiallyimmediately following ingestion of the dosage form, a second groupreleases drug approximately 3-5 hours following ingestion, and anoptional third group provides drug release after approximately 7-9hours.

In a further alternative embodiment, the individual dosage units arecompacted in a single tablet, and represent integral but discretesegments thereof (e.g., layers). For example, drug-containing particlesor drug-containing beads can be compressed together into a single tabletusing conventional tabletting means.

As will be appreciated by those skilled in the art and as described inthe pertinent texts and literature, a number of methods are availablefor preparing drug-containing tablets or other dosage units whichprovide a variety of drug release profiles. Such methods include coatinga drug or drug-containing composition, increasing the drug's particlesize, placing the drug within a matrix, and forming complexes of thedrug with a suitable complexing agent.

The delayed release dosage units in the present capsules can beprepared, for example, by coating a drug or a drug-containingcomposition with a selected membrane coating material, typicallyalthough not necessarily a polymeric material. When a coating is used toprovide delayed release dosage units, particularly preferred coatingmaterials comprise bioerodible, gradually hydrolyzable and/or graduallywater-soluble polymers. The “coating weight,” or relative amount ofcoating material per dosage unit, generally dictates the time intervalbetween ingestion and drug release.

Suitable membrane coating materials for effecting delayed releaseinclude, but are not limited to: cellulosic polymers such ashydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, cellulose acetate,cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropylmethyl cellulose phthalate, cellulose ester-etherphthalate, hydroxypropylcellulose phthalate, alkali salts of celluloseacetate phthalate, alkaline earth salts of cellulose acetate phthalate,hydroxypropylmethyl cellulose hexahydrophthalate, cellulose acetatehexahydrophthalate, and carboxymethylcellulose sodium; acrylic acidpolymers and copolymers preferably formed from acrylic acid, methacrylicacid, acrylic acid alkyl esters, methacrylic acid alkyl esters, and thelike, e.g. copolymers of acrylic acid, methacrylic acid, methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate,with a terpolymer of ethyl acrylate, methyl methacrylate andtrimethylammonioethyl methacrylate chloride (sold under the tradenameEudragit RS) particularly preferred; vinyl polymers and copolymers suchas polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate,vinylacetate crotonic acid copolymer, and ethylene-vinyl acetatecopolymers; and shellac, ammoniated shellac, shellac-acetyl alcohol, andshellac n-butyl stearate.

In some cases, it may be desirable for the third tablet or bead orparticle fraction to provide for release of the active agent in thecolon, in which case polymeric or other materials are used that enabledrug release within the colon. These may be selected from theaforementioned list, or other materials may be used as will be known tothose skilled in the art of pharmaceutical formulation and drugdelivery. For example, hydrocolloid gums may be effective to provide forcolonic delivery, e.g., guar gum, locust gum, bena gum, gum tragacanth,and karaya gum (see, e.g., U.S. Pat. No. 5,656,294 to Friend). Othermaterials suitable for effecting colonic drug delivery includepolysaccharides, mucopolysaccharides, and related compounds, e.g.,pectin, arabinogalactose, chitosan, chondroitin sulfate, dextran,galactomannan, and xylan.

Combinations of different coating materials may also be used to coat asingle dosage unit.

To bring about the desired pulsatile release profile for a dosage formcomprised of encapsulated tablets, the first tablet is provided withlittle or no coating material, the second tablet is provided with somedegree of coating material, the coating weight of a third tablet isstill higher, and so on. Analogously, for encapsulated dosage forms inwhich the drug-containing dosage units are beads or particles, a firstfraction of beads or particles is provided with little or no coatingmaterial, a second fraction is provided with some degree of coatingmaterial, the coating weight of a third fraction is still higher, etc.For example, when the dosage form contains three tablets (or,analogously, three groups of drug-containing particles or beads), thefirst tablet, which releases drug substantially immediately, may have atotal coating weight of less than about 10%, preferably less than about8%, the second tablet may have a total coating weight in the range ofapproximately 10% to 30%, preferably 15% to 25%, and the third tablet,if present, may have a total coating weight in the range ofapproximately 15% to 65%, preferably 20% to 65%. The preferred coatingweights for particular coating materials may be readily determined bythose skilled in the art by evaluating individual release profiles fordosage units prepared with different quantities of various coatingmaterials.

Alternatively, the delayed release dosage units, i.e., tablets ordrug-containing particles, may be formulated by dispersing the drugwithin a matrix of a suitable material such as an insoluble plastic, ahydrophilic polymer, or a fatty compound. The insoluble plastic matricesmay be comprised of, for example, polyvinyl chloride or polyethylene.Hydrophilic polymers useful for providing a matrix for a delayed releasedosage unit include, but are not limited to, those described above assuitable coating materials. Fatty compounds for use as a matrix materialinclude, but are not limited to, waxes generally (e.g., carnauba wax)and glyceryl tristearate. Once the active ingredient is mixed with thematrix material, the mixture can be compressed into tablets or processedinto individual drug-containing particles.

The individual dosage units may be provided with colored coatings, witha single color used to identify a tablet or bead or particle fractionhaving a corresponding delayed release profile. That is, for example, ablue coating may be used for the immediate release tablet or bead orparticle fraction, a red coating may be used for the “medium” releasetablet or bead or particle fraction, and the like. In this way, errorsduring manufacture can be easily avoided. The color is introduced byincorporating a pharmaceutically acceptable colorant into the coatingduring coating preparation. The colorant may be either natural orsynthetic. Natural colorants include pigments such as chlorophyll,anattenes, beta-carotene, alizarin, indigo, rutin, hesperidin,quercitin, carminic acid, and 6,6′-dibromoindigo. Synthetic colorantsare dyes, including both acidic dyes and basic dyes, such as nitrosodyes, nitro dyes, azo dyes, oxazines, thiazines, pyrazolones, xanthenes,indigoids, anthraquinones, acridines, rosanilines, phthaleins,quinolines. e.g., a dye or pigment, during preparation of the coatingsolution.

For encapsulated tablets, the weight of each individual tablet in thecapsule is typically in the range of about 10 mg to 150 mg, preferablyin the range of about 25 mg to about 100 mg, and most preferably is inthe range of about 40 mg to 80 mg. The individual tablets are preparedusing conventional means. A preferred method for forming tablets hereinis by direct compression of a powdered, crystalline or granulardrug-containing composition, alone or in combination with diluents,binders, lubricants, disintegrants, colorants or the like. As analternative to direct compression, compressed tablets can be preparedusing wet-granulation or dry-granulation processes. Tablets may also bemolded rather than compressed, starting with a moist material containinga suitable water-soluble lubricant. Preferred tablets herein aremanufactured using compression rather than molding, however.Drug-containing particles or beads are also prepared using conventionalmeans, typically from a fluid dispersion.

Conventional coating procedures and equipment may then be used to coatthe dosage units, i.e., the drug-containing tablets, beads or particles.For example, a delayed release coating composition may be applied usinga coating pan, an airless spray technique, fluidized bed coatingequipment, or the like. For detailed information concerning materials,equipment and processes for preparing tablets, beads and delayed releasedosage forms, reference may be had to Pharmaceutical Dosage Forms:Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989),and to Ansel et al., Pharmaceutical Dosage Forms and Drug DeliverySystems, 6^(th) Ed. (Media, Pa.: Williams & Wilkins, 1995).

Optional components present in the individual drug-containing dosageunits include, but are not limited to, diluents, binders, lubricants,disintegrants, stabilizers, surfactants, coloring agents, and the like.Diluents, also termed “fillers,” are typically necessary to increase thebulk of a tablet so that a practical size is provided for compression.Suitable diluents include, for example, dicalcium phosphate dihydrate,calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride,dry starch, hydrolyzed starches, silicon dioxide, titanium oxide,alumina, talc, microcrystalline cellulose, and powdered sugar. Bindersare used to impart cohesive qualities to a tablet formulation, and thusensure that a tablet remains intact after compression. Suitable bindermaterials include, but are not limited to, starch (including corn starchand pregelatinized starch), gelatin, sugars (including sucrose, glucose,dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural andsynthetic gums, e.g., acacia, tragacanth, sodium alginate,polyvinylpyrrolidone, celluloses, and Veegum, and synthetic polymerssuch as polymethacrylates and polyvinylpyrrolidone. Lubricants are usedto facilitate tablet manufacture; examples of suitable lubricantsinclude, for example, magnesium stearate, calcium stearate, stearicacid, glyceryl behenate, and polyethylene glycol, and are preferablypresent at no more than approximately 1 wt. % relative to tablet weight.Disintegrants are used to facilitate tablet disintegration or “breakup”after administration, and are generally starches, clays, celluloses,algins, gums or crosslinked polymers. Stabilizers are used to inhibit orretard drug decomposition reactions which include, by way of example,oxidative reactions. Surfactants may be anionic, cationic, amphoteric ornonionic surface active agents, with anionic surfactants preferred.Suitable anionic surfactants include, but are not limited to, thosecontaining carboxylate, sulfonate and sulfate ions, associated withcations such as sodium, potassium and ammonium ions. Particularlypreferred surfactants include, but are not limited to: long alkyl chainsulfonates and alkyl aryl sulfonates such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodiumbis-(2-ethylhexyl)-sulfosuccinate; and alkyl sulfates such as sodiumlauryl sulfate. If desired, the tablets may also contain minor amountsof nontoxic auxiliary substances such as wetting or emulsifying agents,pH buffering agents, preservatives, and the like.

As noted earlier herein, the individual drug tablets, beads or particlesare contained within a closed capsule. The capsule material may beeither hard or soft, and as will be appreciated by those skilled in theart of pharmaceutical science, typically comprises a tasteless, easilyadministered and water soluble compound such as gelatin, starch orcellulose. A preferred capsule material is gelatin. The capsules arepreferably sealed, such as with gelatin bands or the like. See, forexample, Remington: The Science and Practice of Pharmacy, NineteenthEdition (Easton, Pa.: Mack Publishing Co., 1995), which describesmaterials and methods for preparing encapsulated pharmaceuticalsdesigned to dissolve shortly after ingestion.

The novel dosage forms provided herein are used to administerd-threo-methylphenidate in a pulsatile release manner. As noted earlierherein, the drug is administered along with a second CNS stimulant. Thesecond CNS stimulant, which may potentiate the effect of thed-threo-methylphenidate, or vice versa, is generally an analeptic agentor psychostimulant.

Preferred CNS stimulants include, but are not limited to: amphetamine(racemic), d-amphetamine, amphetamine and d-amphetamine phosphate,amphetamine and d-amphetamine sulfate, amphetamine and d-amphetaminehydrochloride, amphetamine and d-amphetamine saccharate, and amphetamineand d-amphetamine aspartate, amphetaminil, bemegride, benzphetamine,benzphetamine hydrochloride, brucine, chlorphentermine, clofenciclan,clortermine, deanol acetamidobenzoate, demanyl phosphate, dexoxadrol,diethpropion, doxapram hydrochloride, N-ethylamphetamine, ethamivan,etifelmin, etryptamine, fencamfamine, fenethylline, fenosolone,fenfluramine, flurothyl, hexacyclonate sodium, homocamfin, mazindol,megexamide, methamphetamine, nicotinic agonists, nikethamide, pemoline,pentylenetetrazole, phenidimetrazine, phendimetrazine tartrate,phenmetrazine, phenmetrazine hydrochloride, phentermine, picrotoxin,pipradrol, pipradrol hydrochloride, prolintane, pyrovalerone,racephedrine, racephedrine hydrochloride, andtetrahydrobenzothienopyridines. Pemoline, amphetamine, d-amphetamine andsalts thereof are particularly preferred additional active agents.

The additional active agent or agents may be combined with thed-threo-methylphenidate in a single tablet or bead or particle fractionwithin the capsule, or one or more tablets or bead fractions within thecapsule may comprise the additional active agent without anymethylphenidate. In the former case, the various active agents may bepresent as an admixture in a single dosage unit (e.g., a tablet), or theagents may be physically segregated as in a bilayer tablet, a tablethaving two or more active agent-containing coatings, or the like.Generally, the additional CNS stimulant such as d-amphetamine will beincluded in the first, immediate release tablet or bead or particlefraction, will optionally be present in the second tablet or bead orparticle fraction (and if present, at a lower dose than in the firsttablet or bead or particle fraction), and will not be included in thethird tablet or bead or particle fraction. Ideally, the relative amountsof the active agents in the dosage forms of the invention are asfollows:

First tablet or bead (or particle) fraction: Contains a dose “X” ofd-threo-methylphenidate and a dose “Y” of a second CNS stimulant (e.g.,an analeptic agent such as d-amphetamine), wherein the molar ratio ofX:Y is in the range of approximately 2:1 to 1:2. The dose “X” representsapproximately half of that which would be appropriate for dosage ofd,l-threo-methylphenidate, and is typically in the range ofapproximately 1 mg to 20 mg, preferably 1 mg to 10 mg. When the secondCNS stimulant is d-amphetamine, “Y” is typically in the range ofapproximately 1 mg to 20 mg, preferably 1 mg to 10 mg.

Second tablet or bead (or particle) fraction: Contains a dose ofd-threo-methylphenidate in the range of approximately 0.5X to 2X,preferably 1X to 2X, and a dose of the second CNS stimulant in the rangeof zero to 0.5Y.

Third tablet or bead (or particle) fraction, if present: Contains a doseof d-threo-methylphenidate in the range of approximately 0.25X to 1X,optimally about 0.5X to 1X, and contains none of the second CNSstimulant.

Thus, the second CNS stimulant, present in the first pulse, isoptionally included in the second pulse, and if present, is at a lowerdose (up to half) of the amount in the first pulse. The third tablet orbead or particle fraction should contain a lower dose ofd-threo-methylphenidate than either the first or second pulses, andshould not contain any of the second CNS stimulant. In this way, thepotential for sleep disruption is minimized.

Salts of the active agents used in conjunction with the present dosageforms may be obtained commercially or can be prepared using standardprocedures known to those skilled in the art of synthetic organicchemistry and described, for example, by J. March, Advanced OrganicChemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York:Wiley-Interscience, 1992). Suitable acids for preparing acid additionsalts may be weak acids, medium acids, or strong acids, and include bothorganic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvicacid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, aspartic acid, saccharic acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike, as well as inorganic acids, e.g., hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like.Preparation of basic salts of acid moieties which may be present (e.g.,carboxylic acid groups) are prepared using a pharmaceutically acceptablebase such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,calcium hydroxide, magnesium hydroxide, trimethylamine, or the like.Preparation of esters involves finctionalization of hydroxyl and/orcarboxyl groups which may be present. These esters are typicallyacyl-substituted derivatives of free alcohol groups, i.e., moietieswhich are derived from carboxylic acids of the formula RCOOH where R isalkyl, and preferably is lower alkyl. Pharmaceutically acceptable estersmay be prepared using methods known to those skilled in the art and/ordescribed in the pertinent literature. Amides, prodrugs, and otheranalogs and derivatives can be readily prepared as well, usingconventional means.

Utility:

The novel drug dosage forms are to be administered orally to a mammalianindividual and can be used to administer d-threo-methylphenidate totreat or prevent a variety of disorders, conditions and diseases. Inaccordance with the present invention, administration ofd-threo-methylphenidate along with the second CNS stimulant may becarried out in order to treat any disorder, condition or disease forwhich methylphenidate is generally indicated. Such disorders, conditionsand diseases include, for example, ADD, ADHD, narcolepsy, and acutedepression; methylphenidate may also be used in the treatment ofindividuals suffering from cognitive decline associated with AIDS orAIDS-related conditions, and for mood elevation in terminally illpatients suffering from a disease such as cancer.

For administration of d-threo-methylphenidate, the typical daily dose isin the range of approximately 2.5 mg to 50 mg, preferably 5 mg to 60 mg,although the exact dosage regimen will depend on a number of factors,including age, the general condition of the patient, the particularcondition or disorder being treated, the severity of the patient'scondition or disorder, and the like.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that thedescription above as well as the examples which follow are intended toillustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

Experimental:

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of pharmaceutical formulation,medicinal chemistry, biological testing, and the like, which are withinthe skill of the art. Such techniques are explained fully in theliterature. Preparation of various types of pharmaceutical formulationsare described, for example, in Lieberman et al., cited supra; synthesisof chiral drugs is described, inter alia, in Wilson and Gisvold,Textbook of Organic, Medicinal and Pharmaceutical Chemistry(Lippincott-Raven Publishers, 1991); and Gibaldi and Perrier,Pharmacokinetics (Marcel Dekker, 1982), provides a description of thebiological testing procedures useful to evaluate compounds such as thosedescribed and claimed herein. All patents, patent applications, andpublications mentioned herein, both supra and infra, are herebyincorporated by reference.

In the following examples, efforts have been made to ensure accuracywith respect to numbers used (e.g., amounts, temperature, etc.) but someexperimental error and deviation should be accounted for. Unlessindicated otherwise, temperature is in degrees C and pressure is at ornear atmospheric. All reagents were obtained commercially unlessotherwise indicated.

EXAMPLE 1 Pulsatile Delivery System for Oral Administration of d-threoMethylphenidate and d-Amphetamine

A pulsatile release dosage form for administration ofd-threo-methylphenidate and d-amphetamine is prepared by (1) formulatingthree individual compressed tablets, each having a different releaseprofile, followed by (2) encapsulating the three tablets into a gelatincapsule and then closing and sealing the capsule. The components of thethree tablets are as follows.

Component Function Amount per tablet TABLET 1 (IMMEDIATE RELEASE):d-threo-methylphenidate Active agent 2.5 mg d-amphetamine Active agent2.5 mg Dicalcium phosphate dihydrate Diluent 26.6 mg Microcrystallinecellulose Diluent 26.6 mg Sodium starch glycolate Disintegrant 1.2 mgMagnesium Stearate Lubricant 0.6 mg TABLET 2 (RELEASE DELAYED 3-5 HOURSFOLLOWING ADMINISTRATION): d-threo methylphenidate Active agent 2.5 mgd-amphetamine Active agent 1.25 mg Dicalcium phosphate dihydrate Diluent26.6 mg Microcrystalline cellulose Diluent 26.6 mg Sodium starchglycolate Disintegrant 1.2 mg Magnesium Stearate Lubricant 0.6 mgEudragit RS30D Delayed release 4.76 mg coating material Talc Coatingcomponent 3.3 mg Triethyl citrate Coating component 0.95 mg TABLET 3(RELEASE DELAYED 7-9 HOURS FOLLOWING ADMINISTRATION): d-threomethylphenidate Active agent 2.5 mg Dicalcium phosphate dihydrateDiluent 26.6 mg Microcrystalline cellulose Diluent 26.6 mg Sodium starchglycolate Disintegrant 1.2 mg Magnesium Stearate Lubricant 0.6 mgEudragit RS30D Delayed release 6.34 mg coating material Talc Coatingcomponent 4.4 mg Triethyl citrate Coating component 1.27 mg

The tablets are prepared by wet granulation of the individual drugparticles and other core components as may be done using a fluid-bedgranulator, or are prepared by direct compression of the admixture ofcomponents. Tablet 1 is an immediate release dosage form, releasing theactive agents within 1-2 hours following administration. Tablets 2 and 3are coated with the delayed release coating material as may be carriedout using conventional coating techniques such as spray-coating or thelike. As will be appreciated by those skilled in the art, the specificcomponents listed in the above tables may be replaced with otherfunctionally equivalent components, e.g., diluents, binders, lubricants,fillers, coatings, and the like.

Oral administration of the capsule to a patient will result in a releaseprofile having three pulses, with initial release of thed-threo-methylphenidate and d-amphetamine from the first tablet beingsubstantially immediate, release of the d-threo-methylphenidate andd-amphetamine from the second tablet occurring 3-5 hours followingadministration, and release of the d-threo-methylphenidate from thethird tablet occurring 7-9 hours following administration. BecauseTablet 3 contains a lower dosage of d-threo-methylphenidate than Tablets1 or 2, and no d-amphetamine, the likelihood of sleep disruption issubstantially reduced.

EXAMLE 2

The method of Example 1 is repeated, except that drug-containing beadsare used in place of tablets. A first fraction of beads may be preparedby coating an inert support material such as lactose with the drug whichprovides the first (immediate release) pulse. A second fraction of beadsis prepared by coating immediate release beads with an amount of entericcoating material sufficient to provide a drug release-free period of 3-5hours. A third fraction of beads is prepared by coating immediaterelease beads having half the methylphenidate dose of the first fractionof beads with a greater amount of enteric coating material, sufficientto provide a drug release-free period of 7-9 hours. The three groups ofbeads may be encapsulated as in Example 1, or compressed, in thepresence of a cushioning agent, into a single pulsatile release tablet.

Alternatively, three groups of drug particles may be provided and coatedas above, in lieu of the drug-coated lactose beads.

What is claimed is:
 1. A pulsatile release dosage form for oraladministration of methylphenidate, comprising: (a) a first dosage unitcomprising a first d-threo-methylphenidate dose X and a first dose Y ofa CNS stimulant other than d-threo-methylphenidate that are releasedsubstantially immediately following oral administration of the dosageform to a patient; (b) a second dosage unit comprising a secondd-threo-methylphenidate dose and optionally a second dose of the CNSstimulant, and a means for delaying release of the second doses untilapproximately 3 to 5 hours following administration of the dosage formto a patient; and optionally (c) a third dosage unit comprising a thirdd-threo-methylphenidate dose without the CNS stimulant, and a means fordelaying release of the third dose until approximately 7 to 9 hoursfollowing oral administration of the dosage form to a patient.
 2. Thedosage form of claim 1, wherein said X and said Y have a molar ratio inthe range of approximately 1:2 to 2:1.
 3. The dosage form of claim 2,wherein said X is in the range of approximately 1 mg to 20 mg.
 4. Thedosage form of claim 3, wherein said X is in the range of approximately1 mg to 10 mg.
 5. The dosage form of claim 3, wherein the second dose ofd-threo-methylphenidate is approximately 0.5X to 2X, and the second doseof the CNS stimulant is in the range of zero to approximately 0.5Y. 6.The dosage form of claim 1, wherein the third dosage unit is present. 7.The dosage form of claim 5, wherein the third dosage unit is present. 8.The dosage form of claim 7, wherein the third dose ofd-threo-methylphenidate is approximately 0.25X to 1X.
 9. The dosage formof claim 6, wherein the first, second and third dosage units are housedin a closed capsule.
 10. The dosage form of claim 6, wherein the first,second and third dosage units represent integral and discrete segmentsof a single tablet.
 11. The dosage form of claim 9, wherein each dosageunit comprises a compressed tablet.
 12. The dosage form of claim 9,wherein each dosage unit comprises a plurality of drug-containing beads.13. The dosage form of claim 9, wherein each dosage unit comprises aplurality of drug-containing particles.
 14. The dosage form of claim 6,wherein the third dosage unit releases the third d-threo-methylphenidatedose in the colon.
 15. The dosage form of claim 1, wherein the CNSstimulant is an analeptic agent.
 16. The dosage form of claim 1, whereinthe CNS stimulant is selected from the group consisting of amphetamine,d-amphetamine, amphetaminil, bemegride, benzphetamine, benzphetamine,brucine, chlorphentermine, clofenciclan, clortermine, deanolacetamidobenzoate, demanyl, dexoxadrol, diethpropion, doxapram,N-ethylamphetamine, ethamivan, etifelmin, etryptamine, fencamfamine,fenethylline, fenosolone, fenfluramine, flurothyl, hexacyclonate,homocamfin, mazindol, megexamide, methamphetamine, nicotinic agonists,nikethamide, pemoline, pentylenetetrazole, phenidimetrazine,phendimetrazine, phenmetrazine, phenmetrazine, phentermine, picrotoxin,pipradrol, prolintane, pyrovalerone, racephedrine,tetrahydrobenzothienopyridines, and pharmacologically acceptable saltsthereof.
 17. The dosage form of claim 16, wherein the CNS stimulant isselected from the group consisting of amphetamine, d-amphetamine, andpharmacologically acceptable salts thereof.
 18. The dosage form of claim17, wherein the CNS stimulant is selected from the group consisting ofamphetamine, d-amphetamine, amphetamine phosphate, d-amphetaminephosphate, amphetamine sulfate, d-amphetamine sulfate, amphetaminehydrochloride, d-amphetamine hydrochloride, amphetamine saccharate,d-amphetamine saccharate, amphetamine aspartate, d-amphetamineaspartate, and combinations thereof.
 19. The dosage form of claim 16,wherein the CNS stimulant is pemoline.
 20. The dosage form of claim 1,wherein the means for delaying release comprises a coating of a delayedrelease membrane material.
 21. The dosage form of claim 20, wherein thedelayed release membrane material is comprised of a bioerodible,hydrolyzable and/or gradually water-soluble polymer.
 22. The dosage formof claim 21, wherein the delayed release membrane material is an acrylicresin.
 23. The dosage form of claim 22, wherein the delayed releasemembrane material is a copolymer of acrylic acid, methacrylic acid,methyl acrylate, ethyl acrylate, methyl methacrylate, ethylmethacrylate, and/or derivatives thereof.
 24. The dosage form of claim22, wherein the delayed release membrane material is a terpolymer ofethyl acrylate, methyl methacrylate and trimethylammonioethylmethacrylate chloride.
 25. The dosage form of claim 1, wherein at leastone of the first, second and third dosage units further comprises adiluent.
 26. The dosage form of claim 25, wherein the diluent isselected from the group consisting of dicalcium phosphate dihydrate,calcium sulfate, lactose, cellulose, kaolin, mannitol, dry starch,hydrolyzed starches, silicon dioxide, titanium oxide, alumina, talc,microcrystalline cellulose, powdered sugar, and mixtures thereof. 27.The dosage form of claim of claim 1, wherein at least one of the first,second and third dosage units further comprises a lubricant.
 28. Thedosage form of claim 27, wherein the lubricant is selected from thegroup consisting of magnesium stearate, calcium stearate, stearic acid,glyceryl behenate, polyethylene glycol, and mixtures thereof.
 29. Thedosage from of claim 28, wherein the lubricant is magnesium stearate.30. The dosage form of claim 1, wherein at least one of the first,second and third dosage units further comprises a disintegrant.
 31. Thedosage form of claim 30, wherein the disintegrant is sodium starchglycolate.
 32. The dosage form of claim 1, wherein each dosage unit hasa different color.
 33. A method for treating an individual sufferingfrom ADD, comprising administering to the individual, once daily, thedosage form of claim
 1. 34. A method for treating an individualsuffering from ADHD, comprising administering to the individual, oncedaily, the dosage form of claim
 1. 35. A method for treating anindividual suffering from narcolepsy, comprising administering to theindividual, once daily, the dosage form of claim
 1. 36. A method fortreating an individual suffering from acute depression, comprisingadministering to the individual, once daily, the dosage form of claim 1.37. A method for treating an individual suffering from cognitive declineassociated with Acquired Immunodeficiency Syndrome (“AIDS”) orAIDS-related conditions, comprising administering to the individual,once daily, the dosage form of claim
 1. 38. A method for elevating themood of a terminally ill patient, comprising administering to thepatient, once daily, the dosage form of claim 1.